tbuckley/cabot-search huggingface dataset:
Sodium-Glucose Cotransporter 2 Inhibitors vs Incretin-Based Drugs and Risk of Fractures for Type 2 Diabetes
Authors: Hwa Yeon Ko, Sungho Bea, Han Eol Jeong, Sohee Park, Young Min Cho, Sung Hye Kong, Ju-Young Shin
Journal: JAMA Network Open (2023)

Importance Postmenopausal individuals with type 2 diabetes are susceptible to fractures due to the interaction of elevated blood glucose levels and a deficiency of the hormone estrogen. Despite continued concerns of fracture risks associated with sodium-glucose cotransporter 2 inhibitors (SGLT2i), existing evidence in this high-risk population is lacking. Objective To assess the risk of fractures associated with SGLT2i vs incretin-based drugs of dipeptidyl-peptidase 4 inhibitors (DPP4i) and glucagon-like peptide 1 receptor agonists (GLP1RA), separately, in postmenopausal individuals with type 2 diabetes. Design, Setting, and Participants This active-comparator, new-user cohort study used nationwide claims data of Korea and took place from January 1, 2013, to December 31, 2020. Postmenopausal individuals (aged ≥45 years) with type 2 diabetes were included. Exposures New users of SGLT2i or comparator drugs. Main Outcomes and Measures The primary outcome was overall fractures, comprising vertebral, hip, humerus, and distal radius fractures. Patients were followed up from the day after drug initiation until the earliest of outcome occurrence, drug discontinuation (90-day grace period) or switch, death, or end of the study period. After propensity score fine stratification, hazard ratios (HRs) with 95% CIs were estimated using weighted Cox models. Results Among 37 530 (mean [SD] age, 60.6 [9.7] years) and 332 004 (mean [SD] age, 60.6 [9.9] years) new users of SGLT2i and DPP4i, respectively, a lower rate of incident overall fractures was presented with SGLT2i vs DPP4i (weighted HR, 0.78; 95% CI, 0.72-0.84). Among 111 835 (mean [SD] age, 61.4 [9.8] years) and 8177 (mean [SD] age, 61.1 [10.3] years) new users of SGLT2i and GLP1RA, respectively, no association with an increased risk of overall fractures was presented with SGLT2i vs GLP1RA (weighted HR, 0.92; 95% CI, 0.68-1.24). Results from several subgroup and sensitivity analyses presented consistent results from main analysis. Conclusions and relevance This population-based cohort study suggests that SGLT2i was not associated with an increased rate of incident fractures compared with DPP4i and GLP1RA, separately, among postmenopausal individuals with type 2 diabetes.
ACC/AHA Hypertension Guidelines and CHA<sub>2</sub>DS<sub>2</sub>-VASc Up-Scoring in Patients With Atrial Fibrillation
Authors: Krishna Pundi, Kensey L. Gosch, Alexander C. Perino, Philip G. Jones, Nihar R. Desai, Thomas M. Maddox, Mintu Turakhia
Journal: JAMA Network Open (2023)

This cohort study compares rates of hypertension among nonhypertensive patients with atrial fibrillation using JNC 8 vs ACC/AHA thresholds.
A redox-responsive nanosystem to suppress chemoresistant lung cancer through targeting STAT3
Authors: Qiyi Feng, Jie Chen, Jinxing Huang, Xiaojie Li, Xinyi Liu, Chunxiu Xiao, Xiuli Zheng, Xuanming Chen, Jue Li, Zhongwei Gu, Kui Luo, Kai Xiao, Weimin Li
Journal: Journal of Controlled Release (2023)
The catalytic subunit of DNA-PK regulates transcription and splicing of AR in advanced prostate cancer
Authors: Beth Adamson, Nicholas Brittain, Laura Walker, Ruaridh Duncan, Sara Luzzi, Pasquale Rescigno, Graham Smith, Suzanne McGill, Richard J.S. Burchmore, Elaine Willmore, Ian Hickson, Craig N. Robson, Denisa Bogdan, Juan M. Jimenez-Vacas, Alec Paschalis, Jonathan Welti, Wei Yuan, Stuart R. McCracken, Rakesh Heer, Adam Sharp, Johann S. de Bono, Luke Gaughan
Journal: Journal of Clinical Investigation (2023)

Aberrant androgen receptor (AR) signaling drives prostate cancer (PC), and it is a key therapeutic target. Although initially effective, the generation of alternatively spliced AR variants (AR-Vs) compromises efficacy of treatments. In contrast to full-length AR (AR-FL), AR-Vs constitutively activate androgenic signaling and are refractory to the current repertoire of AR-targeting therapies, which together drive disease progression. There is an unmet clinical need, therefore, to develop more durable PC therapies that can attenuate AR-V function. Exploiting the requirement of coregulatory proteins for AR-V function has the capacity to furnish tractable routes for attenuating persistent oncogenic AR signaling in advanced PC. DNA-PKcs regulates AR-FL transcriptional activity and is upregulated in both early and advanced PC. We hypothesized that DNA-PKcs is critical for AR-V function. Using a proximity biotinylation approach, we demonstrated that the DNA-PK holoenzyme is part of the AR-V7 interactome and is a key regulator of AR-V-mediated transcription and cell growth in models of advanced PC. Crucially, we provide evidence that DNA-PKcs controls global splicing and, via RBMX, regulates the maturation of AR-V and AR-FL transcripts. Ultimately, our data indicate that targeting DNA-PKcs attenuates AR-V signaling and provide evidence that DNA-PKcs blockade is an effective therapeutic option in advanced AR-V-positive patients with PC.
The US Economic Burden of Health Inequities—Reply
Authors: Thomas A. LaVeist, Darrell J. Gaskin
Journal: JAMA (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Suicide Risks of Health Care Workers in the US
Authors: Mark Olfson, Candace M. Cosgrove, Melanie M. Wall, Carlos Blanco
Journal: JAMA (2023)

Importance Historically elevated risks of suicide among physicians may have declined in recent decades. Yet there remains a paucity of information concerning suicide risks among other health care workers. Objective To estimate risks of death by suicide among US health care workers. Design, Setting, and Participants Cohort study of a nationally representative sample of workers from the 2008 American Community Survey (N = 1 842 000) linked to National Death Index records through December 31, 2019. Main Outcomes and Measures Age- and sex-standardized suicide rates were estimated for 6 health care worker groups (physicians, registered nurses, other health care–diagnosing or treating practitioners, health technicians, health care support workers, social/behavioral health workers) and non–health care workers. Cox models estimated hazard ratios (HRs) of suicide for health care workers compared with non–health care workers using adjusted HRs for age, sex, race and ethnicity, marital status, education, and urban or rural residence. Results Annual standardized suicide rates per 100 000 persons (median age, 44 [IQR, 35-53] years; 32.4% female [among physicians] to 91.1% [among registered nurses]) were 21.4 (95% CI, 15.4-27.4) for health care support workers, 16.0 (95% CI, 9.4-22.6) for registered nurses, 15.6 (95% CI, 10.9-20.4) for health technicians, 13.1 (95% CI, 7.9-18.2) for physicians, 10.1 (95% CI, 6.0-14.3) for social/behavioral health workers, 7.6 (95% CI, 3.7-11.5) for other health care–diagnosing or treating practitioners, and 12.6 (95% CI, 12.1-13.1) for non–health care workers. The adjusted hazards of suicide were increased for health care workers overall (adjusted HR, 1.32 [95% CI, 1.13-1.54]), health care support workers (adjusted HR, 1.81 [95% CI, 1.35-2.42]), registered nurses (adjusted HR, 1.64 [95% CI, 1.21-2.23]), and health technicians (adjusted HR, 1.39 [95% CI, 1.02-1.89]), but adjusted hazards of suicide were not increased for physicians (adjusted HR, 1.11 [95% CI, 0.71-1.72]), social/behavioral health workers (adjusted HR, 1.14 [95% CI, 0.75-1.72]), or other health care–diagnosing or treating practitioners (adjusted HR, 0.61 [95% CI, 0.36-1.03) compared with non–health care workers (reference). Conclusions Relative to non–health care workers, registered nurses, health technicians, and health care support workers in the US were at increased risk of suicide. New programmatic efforts are needed to protect the mental health of these US health care workers.
Overall Survival Among Patients With De Novo Stage IV Metastatic and Distant Metastatic Recurrent Non–Small Cell Lung Cancer
Authors: Chloe C. Su, Julie T. Wu, Eunji Choi, Nathaniel J. Myall, Joel W. Neal, Allison W. Kurian, Henning Stehr, Douglas Wood, Solomon M. Henry, Leah M. Backhus, Ann N. Leung, Heather A. Wakelee, Summer S. Han
Journal: JAMA Network Open (2023)

Importance Despite recent breakthroughs in therapy, advanced lung cancer still poses a therapeutic challenge. The survival profile of patients with metastatic lung cancer remains poorly understood by metastatic disease type (ie, de novo stage IV vs distant recurrence). Objective To evaluate the association of metastatic disease type on overall survival (OS) among patients with non–small cell lung cancer (NSCLC) and to identify potential mechanisms underlying any survival difference. Design, Setting, and Participants Cohort study of a national US population based at a tertiary referral center in the San Francisco Bay Area using participant data from the National Lung Screening Trial (NLST) who were enrolled between 2002 and 2004 and followed up for up to 7 years as the primary cohort and patient data from Stanford Healthcare (SHC) for diagnoses between 2009 and 2019 and followed up for up to 13 years as the validation cohort. Participants from NLST with de novo metastatic or distant recurrent NSCLC diagnoses were included. Data were analyzed from January 2021 to March 2023. Exposures De novo stage IV vs distant recurrent metastatic disease. Main Outcomes and Measures OS after diagnosis of metastatic disease. Results The NLST and SHC cohort consisted of 660 and 180 participants, respectively (411 men [62.3%] vs 109 men [60.6%], 602 White participants [91.2%] vs 111 White participants [61.7%], and mean [SD] age of 66.8 [5.5] vs 71.4 [7.9] years at metastasis, respectively). Patients with distant recurrence showed significantly better OS than patients with de novo metastasis (adjusted hazard ratio [aHR], 0.72; 95% CI, 0.60-0.87; P &amp;amp;lt; .001) in NLST, which was replicated in SHC (aHR, 0.64; 95% CI, 0.43-0.96; P = .03). In SHC, patients with de novo metastasis more frequently progressed to the bone (63 patients with de novo metastasis [52.5%] vs 19 patients with distant recurrence [31.7%]) or pleura (40 patients with de novo metastasis [33.3%] vs 8 patients with distant recurrence [13.3%]) than patients with distant recurrence and were primarily detected through symptoms (102 patients [85.0%]) as compared with posttreatment surveillance (47 patients [78.3%]) in the latter. The main finding remained consistent after further adjusting for metastasis sites and detection methods. Conclusions and Relevance In this cohort study, patients with distant recurrent NSCLC had significantly better OS than those with de novo disease, and the latter group was associated with characteristics that may affect overall survival. This finding can help inform future clinical trial designs to ensure a balance for baseline patient characteristics.
Glucagon-like peptide-1 receptor blockade impairs islet secretion and glucose metabolism in humans
Authors: Andrew A. Welch, Rahele A. Farahani, Aoife M. Egan, Marcello C. Laurenti, Maya Zeini, Max Vella, Kent R. Bailey, Claudio Cobelli, Chiara Dalla Man, Aleksey Matveyenko, Adrian Vella
Journal: Journal of Clinical Investigation (2023)

Background: Proglucagon can be processed to Glucagon-Like Peptide-1 (GLP-1) within the islet but its contribution to islet function in humans remains unknown. We sought to understand whether 'pancreatic' GLP-1 alters islet function in humans and whether this is affected by type 2 diabetes.Methods: We therefore studied individuals with and without type 2 diabetes on 2 occasions in random order. On one occasion exendin 9-39, a competitive antagonist of the GLP-1 Receptor (GLP1R), was infused, while on the other saline was infused. The tracer dilution technique ([3-3H] glucose) was used to measure glucose turnover during fasting and during a hyperglycemic clamp.Results: Exendin 9-39 increased fasting glucose concentrations; fasting islet hormone concentrations were unchanged, but inappropriate for the higher fasting glucose observed. In people with type 2 diabetes fasting glucagon concentrations were markedly elevated and persisted despite hyperglycemia. This impaired suppression of endogenous glucose production by hyperglycemia. These data show that GLP1R blockade impairs islet function, implying that intra-islet GLP1R activation alters islet responses to glucose and does so to a greater degree in people with type 2 diabetes.
Clinical Care for People Who Survive Childhood Cancer
Authors: Smita Bhatia, Emily S. Tonorezos, Wendy Landier
Journal: JAMA (2023)

An estimated 15 000 children and adolescents aged 0 to 19 years are diagnosed with cancer each year in the US, and more than 85% survive for at least 5 years. By 45 years of age, approximately 95% of people who survive childhood cancer will develop a significant health problem related to the childhood cancer diagnosis or its treatment.
Alcohol Use and Sustained Virologic Response to Hepatitis C Virus Direct-Acting Antiviral Therapy
Authors: Emily J. Cartwright, Chloe Pierret, Caroline Minassian, Denise A. Esserman, Janet P. Tate, Matthew B. Goetz, Debika Bhattacharya, David A. Fiellin, Amy C. Justice, Vincent Lo Re, Christopher T. Rentsch
Journal: JAMA Network Open (2023)

Importance Some payers and clinicians require alcohol abstinence to receive direct-acting antiviral (DAA) therapy for chronic hepatitis C virus (HCV) infection. Objective To evaluate whether alcohol use at DAA treatment initiation is associated with decreased likelihood of sustained virologic response (SVR). Design, Setting, and Participants This retrospective cohort study used electronic health records from the US Department of Veterans Affairs (VA), the largest integrated national health care system that provides unrestricted access to HCV treatment. Participants included all patients born between 1945 and 1965 who were dispensed DAA therapy between January 1, 2014, and June 30, 2018. Data analysis was completed in November 2020 with updated sensitivity analyses performed in 2023. Exposure Alcohol use categories were generated using responses to the Alcohol Use Disorders Identification Test–Consumption (AUDIT-C) questionnaire and International Classification of Diseases, Ninth Revision and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision diagnoses for alcohol use disorder (AUD): abstinent without history of AUD, abstinent with history of AUD, lower-risk consumption, moderate-risk consumption, and high-risk consumption or AUD. Main Outcomes and Measures The primary outcome was SVR, which was defined as undetectable HCV RNA for 12 weeks or longer after completion of DAA therapy. Multivariable logistic regression was used to estimate odds ratios (ORs) and 95% CIs of SVR associated with alcohol category. Results Among 69 229 patients who initiated DAA therapy (mean [SD] age, 62.6 [4.5] years; 67 150 men [97.0%]; 34 655 non-Hispanic White individuals [50.1%]; 28 094 non-Hispanic Black individuals [40.6%]; 58 477 individuals [84.5%] with HCV genotype 1), 65 355 (94.4%) achieved SVR. A total of 32 290 individuals (46.6%) were abstinent without AUD, 9192 (13.3%) were abstinent with AUD, 13 415 (19.4%) had lower-risk consumption, 3117 (4.5%) had moderate-risk consumption, and 11 215 (16.2%) had high-risk consumption or AUD. After adjustment for potential confounding variables, there was no difference in SVR across alcohol use categories, even for patients with high-risk consumption or AUD (OR, 0.95; 95% CI, 0.85-1.07). There was no evidence of interaction by stage of hepatic fibrosis measured by fibrosis-4 score ( P for interaction = .30). Conclusions and Relevance In this cohort study, alcohol use and AUD were not associated with lower odds of SVR. Restricting access to DAA therapy according to alcohol use creates an unnecessary barrier to patients and challenges HCV elimination goals.
The Mind, It Strays in the Dark
Authors: Noah M. Raizman
Journal: JAMA (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Global Variations in Heart Failure
Authors: Taher Entezari-Maleki
Journal: JAMA (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Exploring the inhibitory potential of the antiarrhythmic drug amiodarone against <i>Clostridioides difficile</i> toxins TcdA and TcdB
Authors: Judith Schumacher, Astrid Nienhaus, Sebastian Heber, Jauheni Matylitsky, Esteban Chaves-Olarte, César Rodríguez, Holger Barth, Panagiotis Papatheodorou
Journal: Gut Microbes (2023)

The intestinal pathogen Clostridioides difficile is the leading cause of antibiotic-associated diarrhea and pseudomembranous colitis in humans. The symptoms of C. difficile-associated diseases (CDADs) are directly associated with the pathogen's toxins TcdA and TcdB, which enter host cells and inactivate Rho and/or Ras GTPases by glucosylation. Membrane cholesterol is crucial during the intoxication process of TcdA and TcdB, and likely involved during pore formation of both toxins in endosomal membranes, a key step after cellular uptake for the translocation of the glucosyltransferase domain of both toxins from endosomes into the host cell cytosol. The licensed drug amiodarone, a multichannel blocker commonly used in the treatment of cardiac dysrhythmias, is also capable of inhibiting endosomal acidification and, as shown recently, cholesterol biosynthesis. Thus, we were keen to investigate invitro with cultured cells and human intestinal organoids, whether amiodarone preincubation protects from TcdA and/or TcdB intoxication. Amiodarone conferred protection against both toxins independently and in combination as well as against toxin variants from the clinically relevant, epidemic C. difficile strain NAP1/027. Further mechanistic studies suggested that amiodarone's mode-of-inhibition involves also interference with the translocation pore of both toxins. Our study opens the possibility of repurposing the licensed drug amiodarone as a novel pan-variant antitoxin therapeutic in the context of CDADs.
Type I interferon signature and cycling lymphocytes in macrophage activation syndrome
Authors: Zhengping Huang, Kailey E. Brodeur, Liang Chen, None Du, Holly Wobma, Evan E. Hsu, Meng Liu, Joyce C. Chang, Margaret H. Chang, Janet Chou, Megan Day-Lewis, Fatma Dedeoglu, Olha Halyabar, James A. Lederer, Tianwang Li, Mindy S. Lo, Meiping Lu, Esra Meidan, Jane W. Newburger, Adrienne G. Randolph, Mary Beth Son, Robert P. Sundel, Maria L. Taylor, Huaxiang Wu, Qing Zhou, Scott W. Canna, Kevin Wei, Lauren A. Henderson, Peter A. Nigrovic, Pui Y. Lee
Journal: Journal of Clinical Investigation (2023)

BACKGROUNDMacrophage activation syndrome (MAS) is a life-threatening complication of Still's disease (SD) characterized by overt immune cell activation and cytokine storm. We aimed to further understand the immunologic landscape of SD and MAS.METHODWe profiled PBMCs from people in a healthy control group and patients with SD with or without MAS using bulk RNA-Seq and single-cell RNA-Seq (scRNA-Seq). We validated and expanded the findings by mass cytometry, flow cytometry, and in vitro studies.RESULTSBulk RNA-Seq of PBMCs from patients with SD-associated MAS revealed strong expression of genes associated with type I interferon (IFN-I) signaling and cell proliferation, in addition to the expected IFN-γ signal, compared with people in the healthy control group and patients with SD without MAS. scRNA-Seq analysis of more than 65,000 total PBMCs confirmed IFN-I and IFN-γ signatures and localized the cell proliferation signature to cycling CD38+HLA-DR+ cells within CD4+ T cell, CD8+ T cell, and NK cell populations. CD38+HLA-DR+ lymphocytes exhibited prominent IFN-γ production, glycolysis, and mTOR signaling. Cell-cell interaction modeling suggested a network linking CD38+HLA-DR+ lymphocytes with monocytes through IFN-γ signaling. Notably, the expansion of CD38+HLA-DR+ lymphocytes in MAS was greater than in other systemic inflammatory conditions in children. In vitro stimulation of PBMCs demonstrated that IFN-I and IL-15 - both elevated in MAS patients - synergistically augmented the generation of CD38+HLA-DR+ lymphocytes, while Janus kinase inhibition mitigated this response.CONCLUSIONMAS associated with SD is characterized by overproduction of IFN-I, which may act in synergy with IL-15 to generate CD38+HLA-DR+ cycling lymphocytes that produce IFN-γ.